In 1990, Gunasekera and co-workers at the Harbor Branch Oceanographic Institute reported the isolation of (+)-discodermolide (1), an architecturally novel metabolite of the marine sponge Discodermia dissoluta (0.002% w/w). (See, Gunasekera, et al., J. Org. Chem. 1990, 55, 4912. Correction: J. Org. Chem. 1991, 56, 1346).

This marine natural product, a potent stabilizer of microtubules, leads to cell cycle arrest, and ultimately apoptosis—a mechanism similar to the anticancer agents paclitaxel and the epothilones (E. ter Haar, R. J. Kowalski, E. Hamel, C. M. Lin, R. E. Longley, S. P. Gunasekera, H. S. Rosenkranz and B. W. Day, Biochemistry, 1996, 35, 243-250. Discodermolide 1 however is only available in small quantities from the sponge Discodermia dissoluta, and neither the producing organism (thought to be a symbiont) has been cultured, nor have the genes responsible for biosynthesis been obtained. Thus, the large quantities required for clinical trial may be obtained through complex total synthesis routes (See (a) A. B. Smith, III, T. J. Beauchamp, T. J.; M. J. LaMarche, M. D. Kaufman, Y. Qui, H. Arimoto, D. R. Jones and K. Kobayashi, J. Am. Chem. Soc., 2000, 122, 8654-8664; (b) A. B. Smith, III, B. S. Freeze, M. Xian and T. Hirose, Org. Lett., 2005, 7, 1825-1828; (c) I. Paterson and G. J. Florence, Eur. J. Org. Chem., 2003, 2193-2208; (d) I. Paterson and I. Lyothier, J. Org. Chem., 2005, 70, 5494-5507; (e) S. J. Mickel, D. Niederer, R. Daeffler, A. Osmani, E. Kuesters, E. Schmid, K. Schaer and R. Gamoni, Org. Process Res. Dev., 2004, 8, 122-130.
Therefore, there is a need for improved compounds and their compositions that mimic or exceed the high level of pharmacological activity of discodermolide, whose preparation involves more readily available materials, higher yield processes and/or simpler synthetic sequences, or whose products represent structurally simpler discodermolide analogues. The present invention is directed to these compounds, their pharmaceutical compositions, and methods of their use as well as other important ends.
Importantly, the congeners of the present invention represent structurally simple discodermolide analogues with nanomolar antiproliferative activity in cell culture. Compared to (+)-discodermolide, these molecules are considerably easier to synthesize, which may reduce the time and cost of a large scale synthesis.